The islet Beta-cell is the key regulatory element of the glucose homeostasis system. Changes in insulin sensitiveity or Beta-cell mass elicit precise adaptations from the remaining Beta-cells so normoglycemia is maintained. How is that accomplished? The paradox is the presumed normal driving force for insulin secretion and Beta-celt mass is glycemic status which is unchanged. Little is known about this fundamental aspect of Beta-cell function. This application continues our studies of the Beta-cell adaptive mechanisms to a reduction in Beta-cell mass such as occurs in evolving type 1 diabetes, likely also type 2 diabetes, using the experimental model of 60% pancreatectomy in normally insulin sensitive rodents. These rats are normoglycemic following the reduction in Beta-cell mass because of a multifacted adaptive response in islet Beta-cells and pancreatic ducts that results in a normal level of insulin. We plan to test a well-defined mechanistic schema for the adaptive responses. Specifically, we propose a regulatory role for glucokinase in the hyperproliferation and enhanced function that characterize the Beta-cell adaptation, for PPARgamma in subsequently restraining the Beta-cell hyperproliferation, and for IRS-2/Akt signaling in the duct-derived islet neogenesis. We will test these hypotheses by performing partial pancreastectomies in mice with genetically altered expression of key elements in the proposed regulatory pathways - glucokinase (Beta-cell specific knockout), PPARgamma (Beta-cell specific knockout), and IRS-2 (global knockout). These studies will provide a better understanding of the molecular basis for Beta-cell compensation and failure, and they hold considerable promise to provide targets for novel pharmaceutical approaches to the prevention or more effective treatment of type 2 diabetes.